The major long-term goal of the consortium is to improve the management and treatment of brain disorders by identifying and phenotyping mouse models that can be used to develop therapies for such diseases. To reach this goal two major specific aims have to be fulfilled. First, we have to de-velop and implement novel, automated yet intelligent HTP screening technology that allows us to select a single relevant mutant from a collection of thousands; and second, we have to set up a systemic set of LTP screening arrays that allows us to precisely determine the neuropathological phenotype of a selected mouse model at the cellular, microcircuitry and systems level for all four major areas in neuroscience including sensory, motor, cognitive and autonomic systems. Once we have realized these two aims we will subsequently have to standardize the digital analyses and data descriptions of all screens at all levels and communicate the acquired knowledge to academic institutions and commercial customers in terms of both data distribution of phenotype descriptions and of development of techniques and methods. If all these aims are fulfilled, the present consortium may well be able to set the international standard for phenotyping mouse models for brain diseases.

Key objectives
To build a Dutch knowledge platform on mouse phenomics with the aims described under point 2, two series of key objectives will have to be addressed. One category deals with technical and methodological issues, while the other one deals with the scientific outcomes.

 
   
   
 


I. Technical key objectives:

- To determine to what extent the novel video home cage analysis of mouse behaviour improves standardized HTP methods that use serial batteries of fragmented behavioural screen tests.
- To scale up bioassays that are currently being applied at LTP level to a higher capacity.
- To determine which LTP screen methods have to be added to our array to identify and elucidate new pathological mechanisms of brain disorders.

II. Scientific key objectives:

- To determine the phenotypes of mouse models for human brain disorders with single gene defects.
- To determine the phenotypes of mouse models for human brain disorders with multiple gene defects.
- To determine which part of the respective phenotypes reflects a direct effect of the genetic defect and which part is due to secondary compensatory mechanisms.
- To determine which parts of the mouse phenomic map are specific, and which ones are aspecific.

Measurable (economic-societal) deliverables of the project

1. Public Health deliverables

I. new animal models for human brain diseases
II. new patented standardized and non-stratified screening technology for mammalian behaviour
III. new patented screening technologies to develop and test drugs for neuronal function and brain diseases
IV. new avenues to use animal behaviour for food and drug applications in general
V. optimisation of the expensive and inefficient preclinical phase in pharmaceutical in-dustry

2. Economic deliverables

I. animal models for drug development made available to pharmaceutical companies and drug-validation screening for these companies (several Dutch industry partners can be discerned already)
II. screenings for third parties in a joint venture of academia and industry
III. screening procedures, software algorithms and hardware for the life sciences (through Noldus) with the realistic claim of being better, cheaper and faster than the existing technologies
IV. technical, organizational, and logistical knowledge about the operation of a large-scale high-throughput mouse screening facility (through partner, Harlan)
V. cell and neuronal network analysis procedures for the life sciences (through collabora-tions with Till Photonics, Cairn, and P.A.L.M. technologies)
VI. Founding of new screening Neuro-Bsik facility based on the current consortium that will handle HTP mouse screens for third parties on a commercial basis after the four years funding term. This company will continue to identify breed and distribute avail-able mouse lines with neurological/psychiatric phenotypes.

3. Knowledge diffusion

I. All IP will be patented
II. New insights into the mechanisms underlying human and mouse behaviour that will be shared with the international neuroscience community through publications in the best peer-reviewed journals, lectures and symposia, e.g. the biennial international confer-ence Measuring Behavior
III. Training of new researchers in a partially combined new top-master curriculum for (medical) biology, medicine and psychology students of the two participating univer-sities.
IV. Experience with implemented new technology that will be shared with manufacturers
V. Information of the general public on new avenues in drug testing

4. Animal welfare
The protocols presently used for mouse phenotyping require many animals, unnatural testing conditions, unnecessary burden on the animal and frequent contact between the animal and the experimentator. The new protocol is mouse-friendly, does not involve physical restrictions to the animal and can be completed within a few days. Thus, ani-mal welfare is enhanced, while animal use is diminished.